Background: Exosomes are important mediators of intercellular communications and play pivotal roles in cancer progression, metastasis and chemoresistance. CD63 and CD9 are widely accepted exosomal markers. In patients with pancreatic ductal adenocarcinoma (PDAC), positive correlation between CD9 expression and overall survival (OS) was reported. CD63 expression was conserved in all patients with no reported prognostic significance. This study explored the prognostic significance of CD63 and CD9 expression using immunohistochemistry (IHC) in patients with PDAC of mixed racial background. Methods: Between 2012 and 2016, 49 patients with PDAC had available tissues for CD63 and CD9 staining using IHC. Two pathologists independently scored the CD63 and CD9 expression. Staining intensity was graded from 1–3 and staining percentage was estimated in 10% increments. Mean Quick-score (Q-score) (Intensity X Percentage of staining) was calculated. Results: The mean Q-score for CD63 and CD9 are higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites (185 vs. 102, P=0.0002) and (48 vs. 20, P=0.0418) respectively. We fitted Cox proportion hazard regression models to investigate the impact of the covariates CD63 and CD9 on progression free survival (PFS) and OS. CD63 has significant impact on PFS (P=0.0135) and OS (P=0.003). The higher the CD63 Q-score, the longer the PFS and OS. CD9 doesn’t have significant impact on PFS (P=0.5734) or OS (P=0.2682). The mean CD63 and CD9 Q-scores are slightly higher in African American (AA) compared to Caucasians (157 vs. 149, P=0.76) and (45 vs. 29, P=0.43) respectively. Conclusions: CD63 and CD9 expression is higher in primary tumor from the pancreas compared to pancreatic tumor from metastatic sites. There is correlation between CD63 expression (but not CD9 in this cohort) and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC. A trend of higher expression of CD63 and CD9 among AA compared to Caucasians was also noticed.